The teaching of prosthodontic care for older people: a non-rote philosophy

This essay complements that de Baat et al¹ in the last issue with emphasis on the importance of the variability between individual older people. The consequent need for an open minded approach towards planning Prosthodontics is discussed, based on each patient's motivation for aesthetics, function, comfort and self esteem. Both functional expectations and motivation to learn effective health behaviour vary widely, and evaluation of both is essential for realistic planning because further tooth loss and the need for partial dentures occur so frequently. The consequent variation in plans raises the question – which are the strategic teeth to maintain a stable dental occlusion or a future tooth stabilised denture? For undergraduates this demands a non-rote approach to learning.     

Discovery of indazole aldosterone synthase (CYP11B2) inhibitors as potential treatments for hypertension

We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.     

Discovery of potent, orally active benzimidazole glucagon receptor antagonists

The discovery and optimization of potent and selective aminobenzimidazole glucagon receptor antagonists are described. One compound possessing moderate pharmacokinetic properties in multiple preclinical species was orally efficacious at inhibiting glucagon-mediated glucose excursion in transgenic mice expressing the human glucagon receptor, and in rhesus monkeys. The compound also significantly lowered glucose levels in a murine model of diabetes.     

5-Fluorouracil-induced cardiotoxicity mimicking myocardial infarction: a case report

Background  

Severe cardiotoxicity is a documented, but very unusual side-effect of intravenous 5-fluorouracil therapy. The mechanism producing cardiotoxicity is poorly understood.     

P1' oxadiazole protease inhibitors with excellent activity against native and protease inhibitor-resistant HIV-1

HIV-1 protease inhibitors (PI's) bearing 1,3,4-oxadiazoles at the P1' position were prepared by a novel method involving the diastereoselective installation of a carboxylic acid and conversion to the P1' heterocycle. The compounds are picomolar inhibitors of native HIV-1 protease, with most of the compounds maintaining excellent antiviral activity against a panel of PI-resistant strains.     

Characterization of Xenopus cytosolic thyroid-hormone-binding protein (xCTBP) with aldehyde dehydrogenase activity

Multiple cytosolic thyroid-hormone-binding proteins (CTBPs) with varying characteristics, depending on the species and tissue, have been reported. We first purified a 59-kDa CTBP from Xenopus liver (xCTBP), and found that it is responsible for major [125I]T(3)-binding activity in Xenopus liver cytosol. Amino acid sequencing of internal peptide fragments derived from xCTBP demonstrated high identity to the corresponding sequence of mammalian aldehyde dehydrogenases 1 (ALDH1). To confirm whether or not xCTBP is identical to xALDH1, we isolated cDNAs encoding xALDH1 from an adult Xenopus hepatic cDNA library. The amino acid sequences deduced from the two isolated xALDH1 cDNAs were very similar to those of mammalian ALDH1 enzymes. The recombinant xALDH1 protein exhibited both T(3)-binding activity and ALDH activity converting retinal to retinoic acid (RA), which were similar to those of xCTBP purified from liver cytosol. The T(3)-binding activity was inhibited by NAD, while the ALDH activity was inhibited by thyroid hormones. Our results demonstrate that xCTBP is identical to ALDH1 and suggest that this protein might modulate RA synthesis and intracellular concentration of free T(3). Communications between thyroid hormone and retinoid pathways are discussed.